The induction of neuronal phenotype in PC12 cells by NGF is a complex pleiotropic response involving the sequential direct and indirect regulation of a large number of gene products by both posttranslational modification and transcriptional induction. The initial stimulation of the TRK tyrosine kinase subunit of the NGF receptor rapidly leads to the activation of numerous second messenger systems with secondary cascades of interconnected regulatory pathways. Activation of cytoplasmic tyrosine kinases such as sarc are part of this response. Preliminary evidence demonstrates that a relatively early event in the differentiation of PC12 cells is the induction of the neural specific protein tyrosine phosphatase (PTPase) STEP. the purpose of this proposal is to define the potential role of this PTPase in mediating or modulating the pleiotropic response of PC12 cells to NGF by 1) further characterizing the regulation of STEP gene expression, 2) altering the normal abundance of STEP using overexpression and antisense strategies, and 3) identifying the potential physiologic substrates of this PTPase. The applicant is an Assistant Professor in the Department of Pathology, Section of Neuropathology. For the first 3 years of this proposal he will have his own laboratory space near the sponsor's laboratory in the Vollum Institute for Advanced Biomedical Research. For the remainder of the project he will occupy space in the currently developing experimental pathology program located in an adjacent building. The long range goal of this proposal is to establish an independent laboratory for the study of fundamental neurobiologic regulatory processes likely to be important for the understanding of neurodegenerative diseases.
